NEDD4 lactylation promotes APAP induced liver injury through Caspase11 dependent non-canonical pyroptosis

Li, Qinglin; Zhang, Fengping; Wang, Hai; Tong, Yingmu; Fu, Yunong; Wu, Kunjin; Li, Jing; Wang, Cong; Wang, Zi; Jia, Yifan; Chen, Rui; Wu, Yang; Cui, Ruixia; Wu, Yi; Qi, Yun; Qu, Kai; Liu, Chang; Zhang, Jingyao

doi:10.7150/ijbs.91284



Theranostics

International Journal of Medical Sciences

Nanotheranostics

Journal of Cancer

Journal of Genomics

Global reach, higher impact

Full Text | PDF

Int J Biol Sci 2024; 20(4):1413-1435. doi:10.7150/ijbs.91284 This issue Cite

Research Paper

NEDD4 lactylation promotes APAP induced liver injury through Caspase11 dependent non-canonical pyroptosis

Qinglin Li^1,2,3, Fengping Zhang^1,2, Hai Wang^1,2, Yingmu Tong^2,6, Yunong Fu^1,2, Kunjin Wu^2,4, Jing Li^2,4, Cong Wang^1,2, Zi Wang^1,2, Yifan Jia^2,7, Rui Chen^1,2, Yang Wu^1,2, Ruixia Cui^1,2, Yi Wu⁸, Yun Qi^9✉, Kai Qu^2,4✉, Chang Liu^2,4✉, Jingyao Zhang^2,5✉

1. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi 710061, People's Republic of China.
2. Key Laboratory of Surgical Critical Care and Life Support (Xi'an Jiaotong University), Ministry of Education, People's Republic of China.
3. Department of Vascular Surgery, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
4. Department of Hepatobiliary Surgery and Liver Transplantation, The Second Affiliated Hospital of Xi'an Jiaotong University, People's Republic of China.
5. Department of SICU, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi 710061, People's Republic of China.
6. Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi 710061, People's Republic of China.
7. Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi 710061, People's Republic of China.
8. MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an Shaanxi 710061, People's Republic of China.
9. Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi 710061, People's Republic of China.

Citation:

Li Q, Zhang F, Wang H, Tong Y, Fu Y, Wu K, Li J, Wang C, Wang Z, Jia Y, Chen R, Wu Y, Cui R, Wu Y, Qi Y, Qu K, Liu C, Zhang J. NEDD4 lactylation promotes APAP induced liver injury through Caspase11 dependent non-canonical pyroptosis. Int J Biol Sci 2024; 20(4):1413-1435. doi:10.7150/ijbs.91284. https://www.ijbs.com/v20p1413.htm

Other styles

Abstract

Caspase-11 detection of intracellular lipopolysaccharide mediates non-canonical pyroptosis, which could result in inflammatory damage and organ lesions in various diseases such as sepsis. Our research found that lactate from the microenvironment of acetaminophen-induced acute liver injury increased Caspase-11 levels, enhanced gasdermin D activation and accelerated macrophage pyroptosis, which lead to exacerbation of liver injury. Further experiments unveiled that lactate inhibits Caspase-11 ubiquitination by reducing its binding to NEDD4, a negative regulator of Caspase-11. We also identified that lactates regulated NEDD4 K33 lactylation, which inhibits protein interactions between Caspase-11 and NEDD4. Moreover, restraining lactylation reduces non-canonical pyroptosis in macrophages and ameliorates liver injury. Our work links lactate to the exquisite regulation of the non-canonical inflammasome, and provides a basis for targeting lactylation signaling to combat Caspase-11-mediated non-canonical pyroptosis and acetaminophen-induced liver injury.

Keywords: caspase-11, non-canonical pyroptosis, lactate, lactylation, NEDD4.

Citation styles

APA

Li, Q., Zhang, F., Wang, H., Tong, Y., Fu, Y., Wu, K., Li, J., Wang, C., Wang, Z., Jia, Y., Chen, R., Wu, Y., Cui, R., Wu, Y., Qi, Y., Qu, K., Liu, C., Zhang, J. (2024). NEDD4 lactylation promotes APAP induced liver injury through Caspase11 dependent non-canonical pyroptosis. International Journal of Biological Sciences, 20(4), 1413-1435. https://doi.org/10.7150/ijbs.91284.

ACS

Li, Q.; Zhang, F.; Wang, H.; Tong, Y.; Fu, Y.; Wu, K.; Li, J.; Wang, C.; Wang, Z.; Jia, Y.; Chen, R.; Wu, Y.; Cui, R.; Wu, Y.; Qi, Y.; Qu, K.; Liu, C.; Zhang, J. NEDD4 lactylation promotes APAP induced liver injury through Caspase11 dependent non-canonical pyroptosis. Int. J. Biol. Sci. 2024, 20 (4), 1413-1435. DOI: 10.7150/ijbs.91284.

NLM

CSE

Li Q, Zhang F, Wang H, Tong Y, Fu Y, Wu K, Li J, Wang C, Wang Z, Jia Y, Chen R, Wu Y, Cui R, Wu Y, Qi Y, Qu K, Liu C, Zhang J. 2024. NEDD4 lactylation promotes APAP induced liver injury through Caspase11 dependent non-canonical pyroptosis. Int J Biol Sci. 20(4):1413-1435.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.